MPN Zug - Leben mit myeloproliferativen Neoplasien

Episode 8: Understanding and using clinical trials (English version)

July 01, 2024 MPN Dach Region: Schweiz, Österreich, Deutschland Season 2 Episode 8
Episode 8: Understanding and using clinical trials (English version)
MPN Zug - Leben mit myeloproliferativen Neoplasien
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MPN Zug - Leben mit myeloproliferativen Neoplasien
Episode 8: Understanding and using clinical trials (English version)
Jul 01, 2024 Season 2 Episode 8
MPN Dach Region: Schweiz, Österreich, Deutschland

Patients are often confronted with the term "clinical trials". But what do their results mean and what do they tell us specifically about topics such as drug safety? In this episode, Enrica Valentini, an MPN patient herself, interviews Prof. Heinz Gisslinger from the Medical University of Vienna. Prof. Gisslinger explains how MPN patients can understand the results of clinical trials and use them for themselves and gets to the heart of the complex topic in simple terms.

Show Notes Transcript

Patients are often confronted with the term "clinical trials". But what do their results mean and what do they tell us specifically about topics such as drug safety? In this episode, Enrica Valentini, an MPN patient herself, interviews Prof. Heinz Gisslinger from the Medical University of Vienna. Prof. Gisslinger explains how MPN patients can understand the results of clinical trials and use them for themselves and gets to the heart of the complex topic in simple terms.

EV=Enriqua Valentini:
HG= Heinz Gisslinger

0:00 EV
I would like to welcome Professor Gisslinger again today, I am Enriqua Valentini, also suffering from polycythemia vera, and it is a great honor to have this conversation with the Professor. We are going to talk about clinical trials, and I’d like to ask Mr Professor to use a language that is understandable to all of us lay people and I hope that Mr Professor will have an understanding for that. May I go straight to the first question? 
What is a clinical trial?

0:47 HG 
First of all, a warm welcome! I'm delighted to have been invited to this podcast. I am Heinz Gisslinger, still working at the Medical University of Vienna, in the Department of Haematology and Haemostaseology, and I have been working in the field of myeloproliferative neoplasms for decades now. And so, to your question: we started taking part in international trials at an early stage - one of the first and most important trials was a so-called double-blind randomised trial to test whether aspirin has an advantage over placebo in patients with polycythemia vera.

What is such a trial? A trial is usually used to test drugs to see whether certain drugs have an advantage for certain diseases. Before these drugs are generally licensed, i.e. before they receive a general recommendation for use in the case of certain diseases from the authorities, they have to be tested accordingly in the context of such clinical trials. And there are different phases of clinical trials. In a phase 1 study, the tolerability of certain drugs is tested in humans, and it is also checked how high the dose of this drug may be before any serious side effects occur. Participants are always volunteers in this phase 1 study, people for whom it can be assumed that even if side effects occur, they will not cause any serious or permanent damage. Once the dose of this drug has been determined as the highest tolerated or reasonable dose, the study then moves on to phase 2. Here it is tested whether this drug has a specific benefit for this disease. Basically, whether the disease can be treated with this drug in the dose that has now been evaluated, i.e. tested, whether it is well tolerated and can be given over a certain period of time. If this is the case, then this drug is tested in a so-called phase 3 trial. This is the study that, if positive, leads to the drug being authorised by the authorities, in Europe usually by the European Medicines Agency, to determine whether this drug is then approved for this disease. This drug, i.e. a new drug, is tested in these phase 3 trials against the standard therapy, which means that the new drug must be better, more effective and better tolerated to be approved for the treatment of this particular disease. In the context of this first phase 3 trial in polycythemia vera, this was an investigator-initiated trial, in other words it was initiated by the treating physicians, by the clinical researchers, not by a pharmaceutical company. It was about aspirin, which is a commonly available substance, the same as Aspro, but this aspirin was used in one fifth of the usual Aspro dose in this randomised study in polycythemia vera patients. And that was of course not so interesting for the pharmaceutical industry, but it was for our patients, but also for us clinical researchers. Is it better to use aspirin in such a low dose, at the time available in 81 milligrams and now in 100 milligrams in our clinic, compared to a placebo, i.e. an empty drug, an empty powder with no drug in it, and this study clearly showed that aspirin was better at preventing thrombosis, heart attacks, strokes and intermittent claudication compared to no drug, i.e. just an empty drug. And that was a very interesting study, very interesting results, because the outcome was not clear from the outset and if a study like that then produces a very clear result that a drug is better than nothing, in this case the placebo, then the therapy with aspirin has established itself in patients with polycythemia vera. Provided, of course, that there are no contraindications, i.e. no known hypersensitivity to this aspirin from the outset. Since this study, which was also published very prominently in the New England Journal of Medicine, it has become standard practice for aspirin to be used for all patients with polycythemia vera from the beginning. This example of a so-called company-independent (i.e. conducted independently of pharmaceutical companies) randomised double-blind study is a classic example of how a new drug - in this case aspirin, actually an old drug - is introduced as a standard therapy for the treatment of a specific disease. In the case of polycythemia vera, it is extremely important to carry out clinical trials in a controlled setting in order to clearly test the advantage or non-advantage of a new substance group. And then these new substances only come into circulation and our patients are only confronted with such new drugs when we can be fairly sure it has an advantage over the one previously used. Otherwise, it would not pay off for those who finance and conduct these studies to try something like this if it cannot be predicted with a certain probability that such a new drug will be of additional benefit to our patients. Of course, the sponsors of a study like this are also considering whether to start the study at all and, on the other hand, if we know from the beginning that a drug like this is not at all beneficial for our patients, then there is an additional protective mechanism built in, namely the ethics committee, through which all study protocols have to pass. The ethics committee looks at whether such a drug can be beneficial at all, based on previous studies of these new drugs. If this is not the case, then such a study, such a study protocol is disqualified as unethical, as unfeasible and cannot be carried out. It is also a prerequisite that statistical analyses are carried out from the outset. This means calculating the probability that a plausible result will emerge after such a comparison, after such a study. If, after this calculation, the modification is not conclusive enough, the ethics committee can request further statistical calculations, or the ethics committee can also reject such studies from the outset. This means that there is a high degree of certainty for our patients that they will not be burdened with unnecessary stuff, but instead that there is a certain probability that something new will come our way that will bring about an additional improvement in the treatment of certain diseases.

11:47 EV 
That was an incredibly comprehensive explanation. May I ask how long such a study takes?

12:00 HG
It always depends on the study design and on how big the difference is, for example, in the improved efficacy of the new drug compared to the drugs used previously. If this difference is very big, the statistical calculations will of course require fewer patients to show that the advantage is statistically significant. If the difference to the previous medication is not so important, then you need more patients and usually a certain period of treatment so that you can observe the improvement in the disease accordingly. In the case of myeloproliferative diseases, i.e. polycythemia vera, essential thrombocythemia, but also myelofibrosis - these are more chronic diseases where changes do not occur so quickly, so you have to expect a treatment duration of at least 1, often 2, 3, even 4 years in order to find a difference and of course you often have a number of 250 or 300 patients who are included in such a study.

14:08 HG 
So, the calculation of the required number of patients for such a study always results from the calculation of the difference that is to be expected of the new substance compared to the previously established standard therapies. But for new substances in myelofibrosis for example, this figure is usually around 200 to 250 patients, but the number of available patients is of course not very high because we are dealing with a relatively rare disease group in this case. To cut a long story short, these studies usually take about 3 years for those who recruit, i.e. are responsible for the inclusion of new patients, and then the duration of treatment is at least 1 year, if not longer. So, it usually takes 5 years until the study is finished and the results are on the table. That is how long it takes for a new drug to be developed from the first day of the study until the study results are available and then these study results are first submitted to the authorities, who then need a certain amount of time to review the results and then assess them and decide whether this drug should be authorised or not. So, you should reckon with 5-6 years after a drug goes from the laboratory from animal testing into clinical trials and then the so-called phase 3 trial begins. Thus, it takes a long time for this medical progress to be translated into the routine treatment of our patients.

16:26 EV 
So that means the risks of participating in this clinical trial are practically reduced to zero?

16:35 HG
You could say that the risks of participating in such clinical trials are minimal. I wouldn't say reduced to 0. When something new is done, the risk is of course somewhat greater than when something traditional is used. The side effects of the old substance are of course better known, and the new substance has a better chance of being more effective, but the risk is also somewhat greater in the case of a new substance. So, there is a slightly greater risk but also a much greater chance that the disease can be treated better. It's just like in life, a greater benefit in the financial world, which is a good comparison, is of course also associated with a slightly greater risk.

17:40 EV
This means that these examinations extend over several years. If the patients are few and spread all over Austria, what about travelling expenses, parking fees or childcare? Is there any form of reimbursement for these expenses?
18:00 HG 
Yes, patients in clinical trials can usually expect much greater attention in the treating centres, because of course the observation of the disease activity of trial patients is more closely meshed and must be documented accordingly, so that is the great advantage. Disease activity requires much greater attention, and study patients are also followed by more staff, that's one thing. The other is that the costs for the visits when patients come from far away are usually compensated in such studies. We have not had childcare so far, because this is mainly a somewhat older clientele, so childcare is not provided here, but travelling expenses are usually reimbursed by the sponsor of the studies.

19:34 EV
So that means that if I take part in this study, I have preferential treatment because all colleagues working in this specific area are very interested, right? It's understandable, but as a patient, what options do I have to find out that such studies exist so that I can say: ‘I want to take part.’

20:14 HG
Yes, the situation has improved a lot in recent years. It must also be said that the self-help groups have made extremely great progress. Here in Austria, there is a very active and extremely well-functioning self-help group, and internationally there are also increasingly better organised and networked self-help groups, which are of course well informed about the study situation, about the new drugs and also about the centres. They know which studies are running in which centres and where you should go with this particular disease. The advantage for study patients is also that they get in touch with colleagues, i.e. doctors, who have dealt and are dealing intensively with this medical field and are of course very well informed about all possible complications and symptoms in the context of such diseases and have corresponding management experience with this group of diseases.

21:39 EV
If this therapy works for me during the study, can I continue it after the study has ended?  

21:47 HG 
If a very effective substance is given as part of the trial, then this drug is usually not discontinued over a longer period of administration, but if it is not yet approved, it is made available by the sponsor for a certain period of time, and in most cases, it does not take too long until this substance is then approved so that it can also be prescribed. This was the case with JAK-2 inhibitors, for example. With the first JAK-2 inhibitor for the treatment of myelofibrosis, not a single patient was left without this substance before it could be prescribed, and this is an example of how this is usually handled.

22:53 EV 
So that means that I can continue to be treated after the study is concluded?
23:01 HG
Well, you can't promise that 100%, because there are some substances that happen to work extremely well in individual cases but don't manage to get authorisation quickly and here you occasionally have to switch to substitute substances, similar substances that are already authorized. But usually, if a substance works very well, it can then continue to be administered, because you can never leave a patient out in the cold without an effective therapy.

23:53 EV
Your words are very helpful. And what will happen to my medical care if I stop or have to stop participating in this study?

24:12 HG 
It is always evaluated what the advantages and disadvantages of this trial substance are, and this is actually done at every visit. In most cases there is no doubt at all if you can see the progress with the trial substance, but if things go into a direction where you are not sure anymore that the advantages of this particular substance are still given, then treatment is continued in the same centre as part of routine therapy and the patient receives the same attention as in the trial, because it is also necessary to monitor the patient accordingly after discontinuation of such trial medications.

25:13 EV 
In other words, if I'm taking part in the study, that takes place the university setting. What happens when I go to my own personal doctor? Can he then prescribe me similar medication or the same medication?

25:36 HG 
Well, that is only possible if such study medications are already licensed and sometimes that’s a challenge, even if these new drugs are then authorised by the European Medicines Agency, it is important, that this newly authorised specialty for the specific disease is also paid for by the health insurance companies. In Austria we are usually quite well off in this respect; here, such new drugs are authorised relatively quickly on an individual basis. The doctor treating the patient must justify that this new substance has a corresponding benefit. The health insurance companies usually oppose this because these new substances are of course much more expensive than the previous ones, because there is a lot of development costs that need to be recovered for the pharmaceutical industry through routine use. The practitioner must therefore be able to justify the need for this new drug. This is usually only possible in a centre, not by a general practitioner, unless the general practitioners are experts in the treatment of this disease, which is relatively rare in our country.

So, this is a hypothetical case where the patient reaches good results in the trial with this new drug and the pharmaceutical company decides to stop the trial. Is there such a thing? Is such a situation possible?

28:05 HG
One reason why a study is interrupted is because it is realised that the substance is not so good and it is not worth continuing, so that no new patients are exposed to this study or this substance, that is one possibility. This is not so rare. The second possibility is that the substance is so good that expectations are met early on without the calculated number of patients who were intended for treatment in the trial. This means that if, for example, 200 patients were planned to be treated with this new substance as part of the study, and it turns out after 100 patients that the substance is much better than the standard therapy, i.e. the previous therapy for this disease, then the study can also be discontinued. There is one example, another investigator-initiated study, again in polycythemia vera. There is a relatively well-tolerated substance for the treatment of polycythemia. The substance is already registered for the treatment of polycythemia but is being investigated at a very early stage where such drugs are not yet normally available, but only phlebotomies are used - this is a standard procedure in polycythemia. Aspirin, as I have already mentioned, is also a standard procedure in polycythemia and it was seen that the planned 150 patients were not necessary to show the benefit of this new substance in addition to phlebotomy and aspirin, but after 100 patients it was seen that this substance was superior to the standard procedure for newly diagnosed polycythemia that was not yet so severe, and so the study was closed and this was then published and now there is a recommendation to give this substance as early as possible in the course of polycythemia vera, there are also examples of this.

31:04 EV
Very interesting. Perhaps one last question. Is it possible to take part in a study that is being conducted in another country?

31:18 HG
That's a challenge, it's usually not possible. We have also had such a situation in our department, for example, where a patient with myelofibrosis came from a neighbouring country. We are conducting a study with a new JAK-2 inhibitor or an otherwise very effective therapy for myelofibrosis. Is it possible for someone from abroad to come to our centre and can we conduct this study here? Theoretically it is possible in the EU, but in practice we always face endless difficulties. The problem is always in the details, for example that these patients, when routine laboratory tests have to be carried out, do not have Austrian health insurance. These patients then have to pay for all routine tests themselves. Some examinations may have to be carried out more frequently due to the study, even if the study does not specifically require this and therefore these examinations are not paid for as part of the study, but it is still occasionally necessary to do some additional examinations for the safety of our patients. These all have to be paid for by the patients themselves and this has usually not worked, so it's a difficult situation.

33:27 EV
Dear Professor, I have come to the end of my questions to you. Is there anything you would recommend to us?

33:39 HG 
Yes, soon there will be many new drugs for the treatment of myelofibrosis primarily, some new drugs for the treatment of polycythemia vera and some, although not so much, for essential thrombocythemia. I would say that if you don't have the feeling that you get an optimal treatment with your current therapy, you should be a bit alert and look around to see if there are any new opportunities to participate in trials. There will be many opportunities in this regard in the future. You’ll certainly have to be a bit more flexible and sometimes, if a study is not running in your centre, perhaps look to see if another centre runs such a study. You also need to talk openly with the practitioner about whether it is possible to test new substances as part of studies. Flexibility is certainly required here, and a self-help group can provide more assistance by sharing information about the possibilities of participating in studies in the different centres here in Austria.

35:20 EV 
I can only say thank you very, very much. Thank you for passing on your incredible knowledge to us, for allowing us to learn from you how we can go on living and how we can continue to live a normal life. Professor, thank you very, very much.

35:44 HG 
Thank you for the invitation and all the best to you all. Thank you